Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention
Authors: Zhe Wang, Andrew Emmerich, Nicolas J. Pillon, Tim Moore, Daiane Hemerich, Marilyn C. Cornelis, Eugenia Mazzaferro, Siacia Broos, Tarunveer S. Ahluwalia, Traci M. Bartz, Amy R. Bentley, Lawrence F. Bielak, Mike Chong, Audrey Y. Chu, Diane Berry, Rajkumar Dorajoo, Nicole D. Dueker, Elisa Kasbohm, Bjarke Feenstra, Mary F. Feitosa, Christian Gieger, Mariaelisa Graff, Leanne M. Hall, Toomas Haller, Fernando P. Hartwig, David A. Hillis, Ville Huikari, Nancy Heard-Costa, Christina Holzapfel, Anne U. Jackson, Åsa Johansson, Anja Moltke Jørgensen, Marika A. Kaakinen, Robert Karlsson, Kathleen F. Kerr, Boram Kim, Chantal M. Koolhaas, Zoltan Kutalik, Vasiliki Lagou, Penelope A. Lind, Mattias Lorentzon, Leo-Pekka Lyytikäinen, Massimo Mangino, Christoph Metzendorf, Kristine R. Monroe, Alexander Pacolet, Louis Pérusse, Rene Pool, Rebecca C. Richmond, Natalia V. Rivera, Sebastien Robiou-du-Pont, Katharina E. Schraut, Christina-Alexandra Schulz, Heather M. Stringham, Toshiko Tanaka, Alexander Teumer, Constance Turman, Peter J. van der Most, Mathias Vanmunster, Frank J. A. van Rooij, Jana V. van Vliet-Ostaptchouk, Xiaoshuai Zhang, Jing-Hua Zhao, Wei Zhao, Zhanna Balkhiyarova, Marie N. Balslev-Harder, Sebastian E. Baumeister, John Beilby, John Blangero, Dorret I. Boomsma, Soren Brage, Peter S. Braund, Jennifer A. Brody, Marcel Bruinenberg, Ulf Ekelund, Ching-Ti Liu, John W. Cole, Francis S. Collins, L. Adrienne Cupples, Tõnu Esko, Stefan Enroth, Jessica D. Faul, Lindsay Fernandez-Rhodes, Alison E. Fohner, Oscar H. Franco, Tessel E. Galesloot, Scott D. Gordon, Niels Grarup, Catharina A. Hartman, Gerardo Heiss, Jennie Hui, Thomas Illig, Russell Jago, Alan James, Peter K. Joshi, Taeyeong Jung, Mika Kähönen, Tuomas O. Kilpeläinen, Woon-Puay Koh, Ivana Kolcic, Peter P. Kraft, Johanna Kuusisto, Lenore J. Launer, Aihua Li, Allan Linneberg, Jian’an Luan, Pedro Marques Vidal, Sarah E. Medland, Yuri Milaneschi, Arden Moscati, Bill Musk, Christopher P. Nelson, Ilja M. Nolte, Nancy L. Pedersen, Annette Peters, Patricia A. Peyser, Christine Power, Olli T. Raitakari, Mägi Reedik, Alex P. Reiner, Paul M. Ridker, Igor Rudan, Kathy Ryan, Mark A. Sarzynski, Laura J. Scott, Robert A. Scott, Stephen Sidney, Kristin Siggeirsdottir, Albert V. Smith, Jennifer A. Smith, Emily Sonestedt, Marin Strøm, E. Shyong Tai, Koon K. Teo, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Andre G. Uitterlinden, Jagadish Vangipurapu, Natasja van Schoor, Uwe Völker, Gonneke Willemsen, Kayleen Williams, Quenna Wong, Huichun Xu, Kristin L. Young, Jian Min Yuan, M. Carola Zillikens, Alan B. Zonderman, Adam Ameur, Stefania Bandinelli, Joshua C. Bis, Michael Boehnke, Claude Bouchard, Daniel I. Chasman, George Davey Smith, Eco J. C. de Geus, Louise Deldicque, Marcus Dörr, Michele K. Evans, Luigi Ferrucci, Myriam Fornage, Caroline Fox, Theodore Garland, Vilmundur Gudnason, Ulf Gyllensten, Torben Hansen, Caroline Hayward, Bernardo L. Horta, Elina Hyppönen, Marjo-Riitta Jarvelin, W. Craig Johnson, Sharon L. R. Kardia, Lambertus A. Kiemeney, Markku Laakso, Claudia Langenberg, Terho Lehtimäki, Loic Le Marchand, Behrooz Z. Alizadeh, H. Marike Boezen, Lude Franke, Morris Swertz, Cisca Wijmenga, Pim van der Harst, Gerjan Navis, Marianne Rots, Bruce H. R. Wolffenbuttel, Patrik K. E. Magnusson, Nicholas G. Martin, Mads Melbye, Andres Metspalu, David Meyre, Kari E. North, Claes Ohlsson, Albertine J. Oldehinkel, Marju Orho-Melander, Guillaume Pare, Taesung Park, Oluf Pedersen, Brenda W. J. H. Penninx, Tune H. Pers, Ozren Polasek, Inga Prokopenko, Charles N. Rotimi, Nilesh J. Samani, Xueling Sim, Harold Snieder, Thorkild I. A. Sørensen, Tim D. Spector, Nicholas J. Timpson, Rob M. van Dam, Nathalie van der Velde, Cornelia M. van Duijn, Peter Vollenweider, Henry Völzke, Trudy Voortman, Gérard Waeber, Nicholas J. Wareham, David R. Weir, Heinz-Erich Wichmann, James F. Wilson, Andrea L. Hevener, Anna Krook, Juleen R. Zierath, Martine A. I. Thomis, Ruth J. F. Loos, Marcel den Hoed
Journal: Nature Genetics (2022)

Abstract Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type II A muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.